Reinventing Hsp90 Inhibitors: Blocking C‐Terminal Binding Events to Hsp90 by Using Dimerized Inhibitors

Heat shock protein 90 (Hsp90) is a molecular chaperone (90 kDa) that functions as a dimer. This protein facilitates the folding, assembly, and stabilization of more than 400 proteins that are responsible for cancer development and progression. Inhibiting Hsp90’s function will shut down multiple cancer‐driven pathways simultaneously because oncogenic clients rely heavily on Hsp90, which makes this chaperone a promising anticancer target. Classical inhibitors that block the binding of adenine triphosphate (ATP) to the N‐terminus of Hsp90 are highly toxic to cells and trigger a resistance mechanism within cells. This resistance mechanism comprises a large increase in prosurvival proteins, namely, heat shock protein 70 (Hsp70), heat shock protein 27 (Hsp27), and heat shock factor 1 (HSF‐1). Molecules that modulate the C‐terminus of Hsp90 are effective at inducing cancer‐cell death without activating the resistance mechanism. Herein, we describe the design, synthesis, and biological binding affinity for a series of dimerized C‐terminal Hsp90 modulators. We show that dimers of these C‐terminal modulators synergistically inhibit Hsp90 relative to monomers.     

Crosslinkable high dielectric constant polymer dielectrics for low voltage organic field‐effect transistor memory devices

I n this study, we successfully synthesized water/methanol soluble random copolymers with a high dielectric constant, poly(n‐(hydroxymethyl) acrylamide‐co‐5‐(9‐(5‐(diethylamino)pentyl)?2‐(4‐vinylphenyl)?9H‐fluorene(P(NMA‐co‐F6NSt)), which contained chemical crosslinkable segment (NMA) and hole trapping building block (F6NSt). The feeding molar ratios of two monomers (NMA:F6NSt) were set as 100:0, 95:5, 80:20, and 67:33 for the copolymers of P1 , P2 , P3, and P4 , respectively. The crosslinked P(NMA‐co‐F6NSt) thin film could serve as both dielectric and charge storage layers in organic field‐effect transistor (OFET) memory device and exhibited high k (i.e., 4.91–6.47) characteristics, leading to a low voltage operation and a small power consumption. Devices based on the P1 ‐ P4 dielectrics showed excellent insulating properties and good charge storage performance under a low operating voltage in a range of ±5V because of tightly network structures and well‐dispersed trapping cites. In particular, P3 ‐based memory device exhibited a large memory window of 4.13 V with stable data retention stability over 10⁴ s, a large on/off ratio of 10⁴, and good endurance characteristics as high as 200 cycles. The above results suggested that a high‐performance OFET memory device could be facilely achieved using the novel crosslinkable high‐k copolymers. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3224–3236     

Synthesis and characterization of double hydrophilic block copolymers containing semi-rigid and flexible segments

3-Methyl-(E)-stilbene (3MSti) and 4-(diethylamino)-(E)-stilbene (DEASti) monomers are synthesized and polymerized separately with maleic anhydride (MAn) in a strictly alternating fashion using reversible addition-fragmentation chain transfer (RAFT) polymerization techniques. The optimal RAFT chain transfer agents (CTAs) for each copolymerization affect the reaction kinetics and CTA compatibilities. Psuedo-first order polymerization kinetics are demonstrated for the synthesis of poly((3-methyl-(E)-stilbene)-alt-maleic anhydride) (3MSti-alt-MAn) with a thiocarbonylthio CTA (methyl 2-(dodecylthiocarbonothioylthio)−2-methylpropionate, TTCMe). In contrast, a dithioester CTA (cumyl dithiobenzoate, CDB) controls the synthesis of poly((4-(diethylamino)-(E)-stilbene)-alt-maleic anhydride) (DEASti-alt-MAn) with pseudo-first order polymerization kinetics. DEASti-alt-MAn is chain extended with 4-acryloylmorpholine (ACMO) to synthesize diblock copolymers and subsequently converted to a double hydrophilic polyampholyte block copolymers (poly((4-(diethylamino)-(E)-stilbene)-alt-maleic acid))-b-acryloylmorpholine) (DEASti-alt-MA)-b-ACMO) via acid hydrolysis. The isoelectric point and dissociation behavior of these maleic acid-containing copolymers are determined using ζ-potential and acid–base titrations, respectively. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 219–227     

OH+C2H3F的反应机理及产物支化比反应的理论研究

本文对HOC₂H₃F可能解离通道的势能面进行从头算CCSD(T)/CBS//B3LYP/6-311G(d，p)计算，同时对速率常数进行Rice-Ramsperger-Kassel-Marcus计算. 生成主要产物CH₂CHO+HF最有利的反应途径是OHC₂H₃F→i2→TS14→i6→TS9→i3→TS3→CH₂CHO+HF，其中速率决定步骤是HF通过TS11从CO桥接位置解离，能量比反应物高3.8 kcal/mol. 借助中间态TS14，F原子从C_α迁移到C_β位置生成CH₂O+CH₂F，然后通过中间态TS16，H从O迁移到C_α位置；通过中间态TS5，C-C键断裂生成产物，其能量比反应物低1.8 kcal/mol，比TS11低4.0 kcal/mol.     

Spectroscopic and theoretical optical properties of indoleninyl-substituted dibenzotetraaza[14]annulenes

Two new macrocyclic dibenzotetraaza[14]annulene (DBTAA) compounds with indolenine ( 5 ) and pyridoindolenine ( 6 ) moieties were synthesized and characterized by spectroscopy. Both DBTAAs exhibit strong UV-Vis absorption properties in the Soret band region. The theoretical second-order nonlinear optical property, electric dipole moment (μ), dispersion-free dipole polarizability (α) and first hyper-polarizability values were calculated by density functional theory and time dependent density functional theory. The ab-initio quantum mechanical calculation by time-dependent Hartree-Fock method was utilized to investigate the dynamic dipole polarizabilities, dynamic second-order, static, and dynamic third-order (γ) hyper-polarizabilities of the DBTAAs. The configuration interaction technique of all doubly occupied molecular orbitals possesses theoretically defined single-photon absorption (OPA) specifications for the examined structures. The computed maximum OPA wavelengths on both macrocyclic compounds coincide with the preceding measurement outcomes.     

Vitamin A and Bone Health: A Review on Current Evidence

Vitamin A is a fat-soluble micronutrient essential for growth, immunity, and good vision. The preformed retinol is commonly found in food of animal origin whereas provitamin A is derived from food of plant origin. This review summarises the current evidence from animal, human and cell-culture studies on the effects of vitamin A towards bone health. Animal studies showed that the negative effects of retinol on the skeleton were observed at higher concentrations, especially on the cortical bone. In humans, the direct relationship between vitamin A and poor bone health was more pronounced in individuals with obesity or vitamin D deficiency. Mechanistically, vitamin A differentially influenced the stages of osteogenesis by enhancing early osteoblastic differentiation and inhibiting bone mineralisation via retinoic acid receptor (RAR) signalling and modulation of osteocyte/osteoblast-related bone peptides. However, adequate vitamin A intake through food or supplements was shown to maintain healthy bones. Meanwhile, provitamin A (carotene and β-cryptoxanthin) may also protect bone. In vitro evidence showed that carotene and β-cryptoxanthin may serve as precursors for retinoids, specifically all-trans-retinoic acid, which serve as ligand for RARs to promote osteogenesis and suppressed nuclear factor-kappa B activation to inhibit the differentiation and maturation of osteoclasts. In conclusion, we suggest that both vitamin A and provitamin A may be potential bone-protecting agents, and more studies are warranted to support this hypothesis.     

Cleavage of a PN Bond in a Urea‐Containing (Ph2P(R)PPh2)‐Bridged Dinuclear Gold(I) Thiolate Complex by Fluoride and a Mechanistic Insight

A urea‐containing, (Ph₂P(R)PPh₂)‐bridged, dinuclear, gold(I) thiolate complex, [Au₂{Ph₂PN(C₆H₄OMe‐4)PPh₂}(SC₆H₄NHCONHC₆H₅)₂] ( 1 ) was designed and synthesized and its photophysical and anion recognition properties studied. The results show that 1 has a high selectivity toward F^?. Upon addition of F^?, the yellow solution was decolorized, and drastic changes of emission and ¹H and ³¹P{¹H} NMR signals were observed. Interestingly, these changes are attributed to fluoride‐assisted P?N bond hydrolysis, instead of the expected hydrogen‐bonding interactions with the urea receptor. Similar changes were observed for two other basic anions, AcO^? and H₂PO₄^?, but to a much lesser extent; and these anions were found to bind to the urea receptor at the same time. On the other hand, Cl^? was found to only bind to the urea moiety through hydrogen‐bonding interactions. Further studies with the control complex [Au₂{Ph₂PN(C₆H₄OMe‐4)PPh₂}Cl₂] ( 2 ) indicate that F^? assists the hydrolysis process via cleavage of the P?N bond. DFT calculations were performed to study the reaction mechanism for the fluoride‐assisted P?N bond hydrolysis of 2 ; these provide a better insight into the role of fluoride in the hydrolysis.     

Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma

Recent studies have shown that circulating microRNAs are a potential biomarker in various types of malignancies. The aim of this study was to investigate the feasibility of using serum exosomal microRNAs as novel serological biomarkers for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We measured the serum exosomal microRNAs and serum circulating microRNAs in patients with CHB (n=20), liver cirrhosis (LC) (n=20) and HCC (n=20). Serum exosomal microRNA was extracted from 500 μl of serum using an Exosome RNA Isolation kit. The expression levels of microRNAs were quantified by real-time PCR. The expression levels of selected microRNAs were normalized to Caenorhabditis elegans microRNA (Cel-miR-39). The serum levels of exosomal miR-18a, miR-221, miR-222 and miR-224 were significantly higher in patients with HCC than those with CHB or LC (P<0.05). Further, the serum levels of exosomal miR-101, miR-106b, miR-122 and miR-195 were lower in patients with HCC than in patients with CHB (P=0.014, P<0.001, P<0.001 and P<0.001, respectively). There was no significant difference in the levels of miR-21 and miR-93 among the three groups. Additionally, the serum levels of circulating microRNAs showed a smaller difference between HCC and either CHB or LC. This study suggests that serum exosomal microRNAs may be used as novel serological biomarkers for HCC.